The central hypothesis of this project is that abnormalities and disturbances of cardiac sympathetic nerve function play an important role in the pathogenesis or progression of certain cardiovascular disorders, such as congestive heart failure. The aim of this project is to develop and utilize methodologies for comprehensive examination of cardiac sympathetic nerve function in health and disease. Recent work examined how cardiac norepinephrine synthesis is regulated with changes in norepinephrine release from cardiac sympathetic neurons. Differences in arterial and coronary venous plasma concentrations of norepinephrine and its metabolites and of dihydroxyphenylalanine (DOPA), the immediate product of tyrosine hydroxylase, were examined before and during cycling exercise in 11 subjects. Relative exercise-induced increases in tyrosine hydroxylation matched closely corresponding increases in norepinephrine turnover, but were much lower than increases in norepinephrine release. The much larger relative increase in release than turnover of norepinephrine was largely attributable to the extensive contribution to transmitter turnover from intraneuronal metabolism of norepinephrine leaking from storage vesicles. At rest, 85% of cardiac norepinephrine turnover was due to loss of transmitter following metabolism of norepinephrine leaking from vesicles, whereas during sympathetic activation this contribution remained constant and that from loss of transmitter secondary to exocytotic release of norepinephrine increased. These results indicate that during sympathetic activation the proportionate increase in norepinephrine turnover is smaller than that in exocytotic release of norepinephrine so that to replenish the norepinephrine lost from stores, tyrosine hydroxylase activity need increase only in proportion to the smaller increase in turnover rather than the larger increase in release. The ability to "gear down" increases in tyrosine hydroxylation relative to increases in norepinephrine release provides sympathetic nerves with the capacity for a more extended range of sustainable release rates than otherwise possible. Other ongoing studies are examining how cardiac sympathetic nerve function is altered in patients with renovascular hypertension with cardiac hypertrophy and whether improved cardiac function in heart failure patients treated with the beta blocker, metoprolol, is associated with normalization of cardiac sympathetic nerve function.